Carbohydrate antibodies, pharmaceutical compositions and uses thereof

Abstract

The present invention provides antibodies or the antigen-binding portion thereof to a tumor-associate carbohydrate antigen. Also disclosed herein are pharmaceutical compositions and methods for the inhibition of cancer cells in a subject in need thereof. The pharmaceutical compositions comprise an antibody or an antigen-binding portion thereof and at least one pharmaceutically acceptable carrier.

What is claimed is: 
     
       1. A method for inhibiting proliferation of a cancer cell, comprising:
 contacting the cancer cell with an effective amount of an antibody, or antigen-binding portion thereof, that binds to a carbohydrate antigen, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region comprising:
 a heavy chain complementarity determining region HC-CDR1 selected from the group consisting of: 
 (i) SEQ ID NO: 1, 
 (ii) SEQ ID NO: 1 wherein amino acid residue 3 is substituted with an arginine (S028R), and 
 (iii) SEQ ID NO: 1 wherein amino acid residue 6 is substituted with an arginine (T031R), 
 a heavy chain complementarity determining region HC-CDR2 selected from the group consisting of: 
 (i) SEQ ID NO: 2, 
 (ii) SEQ ID NO: 2 wherein amino acid residue 6 is substituted with a glycine (D057G), and 
 
 (iii) SEQ ID NO: 2 wherein amino acid residue 12 is substituted with a tyrosine (P063Y),
 a heavy chain complementarity determining region HC-CDR3 selected from the group consisting of: 
 (i) SEQ ID NO: 3, and 
 (ii) SEQ ID NO: 3 wherein amino acid residue 6 is substituted with an arginine (D105R), 
 a light chain complementarity determining region LC-CDR1 selected from the group consisting of: 
 (i) SEQ ID NO: 7, 
 (ii) SEQ ID NO: 7 wherein amino acid residue 1 is substituted with a tryptophan (R024W), and 
 (iii) SEQ ID NO: 7 wherein amino acid residue 9 is substituted with a glutamine (M032Q), 
 a light chain complementarity determining region LC-CDR2 selected from the group consisting of: 
 (i) SEQ ID NO: 8, 
 (ii) SEQ ID NO: 8 wherein amino acid residue 1 is substituted with a glycine (A049G), and 
 (iii) SEQ ID NO: 8 wherein amino acid residue 5 is substituted with a lysine (L053K), and 
 a light chain complementarity determining region LC-CDR3 selected from the group consisting of: 
 (i) SEQ ID NO: 9, and 
 (ii) SEQ ID NO: 9 wherein amino acid residue 6 is substituted with an arginine (N093R), 
 
 wherein the antibody, or an antigen-binding portion thereof comprises at least one of the amino acid substitutions in a CDR region selected from the group consisting of S028R, T031R, D057G, P063Y, D105R, R024W, M032Q, A049G, L053K and N093R. 
 
     
     
       2. The method of  claim 1 , wherein the antibody or antigen-binding portion thereof further comprises at least one of the following frameworks:
 (a) a heavy chain framework (HC-FW1) having a sequence 90% to 100% homologous to SEQ ID NO: 4, 
 (b) a heavy chain framework (HC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 5, 
 (c) a heavy chain framework (HC-FW3) having a sequence 90% to 100% homologous to SEQ ID NO: 6, 
 (d) a heavy chain framework (HC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 5, wherein amino acid residue 9 in HC-FW2 is glycine and not substituted, 
 (e) a light chain framework (LC-FW1) having a sequence 90% to 100% homologous to SEQ ID NO: 10, 
 (f) a light chain framework (LC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 11, 
 (g) a light chain framework (LC-FW3) having a sequence 90% to 100% homologous to SEQ ID NO: 12, 
 (h) a light chain framework (LC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 11, wherein amino acid residue 12 in LC-FW2 is proline and not substituted, and/or (i) a light chain framework (LC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 11, wherein amino acid residue 13 in LC-FW2 is tryptophan and not substituted. 
 
     
     
       3. The method of  claim 1 , wherein the carbohydrate antigen is Globo H, stage-specific embryonic antigen 3 (SSEA-3), stage-specific embryonic antigen 4 (SSEA-4), Gb4, Gb3, sLe x , Le x , sLe a , Le a , Le y , polysialic acid (PSA), sTn, Tn, TF, GD1, GD2, GD3, Fucosyl GM1, GM1, GM2, GM3, GD1a, GM2, 6Gal-HSO 3 -SiaLe x  or 6GluNAc-HSO 3 -SiaLe x . 
     
     
       4. The method of  claim 1 , wherein the cancer is a Globo H, SSEA-3 or SSEA-4 expressing cancer. 
     
     
       5. The method of  claim 1 , wherein the cancer is selected from the group consisting of sarcomas, skin cancer, leukemia, lymphoma, brain cancer, glioblastoma, lung cancer, breast cancer, oral cancer, head-and-neck cancer, nasopharyngeal cancer, esophageal cancer, stomach cancer, liver cancer, bile duct cancer, gallbladder cancer, bladder cancer, pancreatic cancer, intestinal cancer, colorectal cancer, kidney cancer, cervix cancer, endometrial cancer, ovarian cancer, testicular cancer, buccal cancer, oropharyngeal cancer, laryngeal cancer, hematopoietic cancer and prostate cancer. 
     
     
       6. A method for treating cancer, comprising:
 administering to a subject in need of such treatment an effective amount of a pharmaceutical composition comprising: 
 an antibody, or antigen-binding portion thereof, that binds to a carbohydrate antigen; and 
 a pharmaceutical acceptable carrier, 
 wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain 
 variable region and a light chain variable region comprising:
 a heavy chain complementarity determining region HC-CDR1 selected from the group consisting of: 
 (i) SEQ ID NO: 1, 
 (ii) SEQ ID NO: 1 wherein amino acid residue 3 is substituted with an arginine (S028R), and 
 (iii) SEQ ID NO: 1 wherein amino acid residue 6 is substituted with an arginine (T031R), 
 a heavy chain complementarity determining region HC-CDR2 selected from the group consisting of: 
 (i) SEQ ID NO: 2, 
 (ii) SEQ ID NO: 2 wherein amino acid residue 6 is substituted with a glycine (D057G), and 
 (iii) SEQ ID NO: 2 wherein amino acid residue 12 is substituted with a tyrosine (P063Yl), 
 a heavy chain complementarity determining region HC-CDR3 selected from the group consisting of: 
 (i) SEQ ID NO: 3, and 
 (ii) SEQ ID NO: 3 wherein amino acid residue 6 is substituted with an arginine (D105R), 
 a light chain complementarity determining region LC-CDR1 selected from the group consisting of: 
 (i) SEQ ID NO: 7, 
 (ii) SEQ ID NO: 7 wherein amino acid residue 1 is substituted with a tryptophan (R024W), and 
 (iii) SEQ ID NO: 7 wherein amino acid residue 9 is substituted with a glutamine (M032Q), 
 a light chain complementarity determining region LC-CDR2 selected from the group consisting of: 
 (i) SEQ ID NO: 8, 
 (ii) SEQ ID NO: 8 wherein amino acid residue 1 is substituted with a glycine (A049G), and 
 (iii) SEQ ID NO: 8 wherein amino acid residue 5 is substituted with a lysine (L053K), and 
 a light chain complementarity determining region LC-CDR3 selected from the group consisting of: 
 (i) SEQ ID NO: 9, and 
 (ii) SEQ ID NO: 9 wherein amino acid residue 6 is substituted with an arginine (N093R), 
 wherein the antibody, or an antigen-binding portion thereof, comprises at least one of the amino acid substitutions in a CDR region selected from the group consisting of S028R, T031R, D057G, P063Y, D105R, R024W, M032Q, A049G, L053K and N093R. 
 
 
     
     
       7. The method of  claim 6 , wherein the antibody, or antigen-binding portion thereof, further comprises at least one of the following frameworks:
 (a) a heavy chain framework (HC-FW1) having a sequence 90% to 100% homologous to SEQ ID NO: 4, 
 (b) a heavy chain framework (HC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 5, 
 (c) a heavy chain framework (HC-FW3) having a sequence 90% to 100% homologous to SEQ ID NO: 6, 
 (d) a heavy chain framework (HC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 5, wherein amino acid residue 9 in HC-FW2 is glycine and not substituted, 
 (e) a light chain framework (LC-FW1) having a sequence 90% to 100% homologous to SEQ ID NO: 10, 
 (f) a light chain framework (LC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 11, 
 (g) a light chain framework (LC-FW3) having a sequence 90% to 100% homologous to SEQ ID NO: 12, 
 (h) a light chain framework (LC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 11, wherein amino acid residue 12 in LC-FW2 is proline and not substituted, and/or 
 (i) a light chain framework (LC-FW2) having a sequence 90% to 100% homologous to SEQ ID NO: 11, wherein amino acid residue 13 in LC-FW2 is tryptophan and not substituted. 
 
     
     
       8. The method of  claim 6 , wherein the carbohydrate antigen is Globo H, stage-specific embryonic antigen 3 (SSEA-3), stage-specific embryonic antigen 4 (SSEA-4), Gb4, Gb3, sLe x , Le x , sLe a , Le a , Le y , polysialic acid (PSA), sTn, Tn, TF, GD1, GD2, GD3, Fucosyl GM1, GM1, GM2, GM3, GD1a, GM2, 6Gal-HSO 3 -SiaLe x  or 6GluNAc-HSO 3 -SiaLe x . 
     
     
       9. The method of  claim 6 , wherein the cancer is a Globo H, SSEA-3 or SSEA-4 expressing cancer. 
     
     
       10. The method of  claim 6 , wherein the subject is human. 
     
     
       11. The method of  claim 6 , wherein the cancer is a glioma, meningioma or pituitary adenoma. 
     
     
       12. The method of  claim 6 , wherein the cancer is a CNS metastasis from a systemic cancer. 
     
     
       13. The method of  claim 6 , wherein the cancer is selected from the group consisting of sarcomas, skin cancer, leukemia, lymphoma, brain cancer, glioblastoma, lung cancer, breast cancer, oral cancer, head-and-neck cancer, nasopharyngeal cancer, esophageal cancer, stomach cancer, liver cancer, bile duct cancer, gallbladder cancer, bladder cancer, pancreatic cancer, intestinal cancer, colorectal cancer, kidney cancer, cervix cancer, endometrial cancer, ovarian cancer, testicular cancer, buccal cancer, oropharyngeal cancer, laryngeal cancer, hematopoietic cancer and prostate cancer. 
     
     
       14. The method of  claim 6 , wherein the pharmaceutical composition is administered by intravenous, intramuscular, intranasal, subcutaneous, oral, topical, subcutaneous, intradermal, transdermal, subdermal, parenteral, rectal, spinal, or epidermal administration. 
     
     
       15. The method of  claim 6 , wherein the pharmaceutical composition further comprises at least one therapeutic agent. 
     
     
       16. The method of  claim 15 , wherein the therapeutic agent is a monoclonal antibody, polyclonal antibody or an anti-cancer agent. 
     
     
       17. The method of  claim 16 , wherein the anti-cancer agent is DNA damaging or tubulin binding agents, or agents which inhibit angiogenesis, signal transduction pathways or mitotic checkpoints.